rs118177681

chr15-33844930-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001036.6(RYR3):c.13365G>A(p.Glu4455=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,996 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (11 hom., cov: 33)
  • Exomes 𝑓: 0.011 (131 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.161

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-33844930-G-A is Benign according to our data. Variant chr15-33844930-G-A is described in ClinVar as [Benign]. Clinvar id is 461862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.161 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00882 (1343/152310) while in subpopulation SAS AF= 0.0253 (122/4824). AF 95% confidence interval is 0.0216. There are 11 homozygotes in gnomad4. There are 671 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.13365G>A	p.Glu4455=	synonymous_variant	93/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.13365G>A	p.Glu4455=	synonymous_variant	93/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1344 AN: 152192 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.0113 AC: 2817 AN: 249270 Hom.: 30 AF XY: 0.0125 AC XY: 1685 AN XY: 135232

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00765

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.00446

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0114 AC: 16596 AN: 1461686 Hom.: 131 Cov.: 34 AF XY: 0.0119 AC XY: 8637 AN XY: 727126

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00787

Gnomad4 ASJ exome AF: 0.0228

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0241

Gnomad4 FIN exome AF: 0.00498

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00882 AC: 1343 AN: 152310 Hom.: 11 Cov.: 33 AF XY: 0.00901 AC XY: 671 AN XY: 74476

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.0276

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0113 Hom.: 8

Bravo AF: 0.00830

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	0.69
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs118177681; hg19: chr15-34137131;